High degree of alignment precision associated with total knee arthroplasty performed using a surgical robot or handheld navigation.

PURPOSE: The purpose of this study was to compare the precision of bony resections during total knee arthroplasty (TKA) performed using different computer-assisted technologies. METHODS: Patients who underwent a primary TKA using an imageless accelerometer-based handheld navigation system (KneeAlign2®, OrthAlign Inc.) or computed tomography-based large-console surgical robot (Mako®, Stryker Corp.) from 2017 to 2020 were retrospectively reviewed. Templated alignment targets and demographic data were collected. Coronal plane alignment of the femoral and tibial components and tibial slope were measured on postoperative radiographs. Patients with excessive flexion or rotation preventing accurate measurement were excluded. RESULTS: A total of 240 patients who underwent TKA using either a handheld (n = 120) or robotic (n = 120) system were included. There were no statistically significant differences in age, sex, and BMI between groups. A small but statistically significant difference in the precision of the distal femoral resection was observed between the handheld and robotic cohorts (1.5° vs. 1.1° difference between templated and measured alignments, p = 0.024), though this is likely clinically insignificant. There were no significant differences in the precision of the tibial resection between the handheld and robotic groups (coronal plane 0.9° vs. 1.0°, n.s.; sagittal plane 1.2° vs. 1.1°, n.s.). There were no significant differences in the rate of overall precision between cohorts (n.s.). CONCLUSIONS: A high degree of component alignment precision was observed for both imageless handheld navigation and CT-based robotic cohorts. Surgeons considering options for computer-assisted TKA should take other important factors, including surgical principles, templating software, ligament balancing, intraoperative adjustability, equipment logistics, and cost, into account. LEVEL OF EVIDENCE: III.

Which Combination is the Best? A Comparison of the Predictive Potential of Serum Biomarker Combinations to Diagnose Periprosthetic Joint Infection.

BACKGROUND: Without a gold-standard test, recent periprosthetic joint infections (PJI) literature has explored the utility of combining serological results, with promising findings. However, previous studies evaluated fewer than 200 patients and often studied only 1 to 2 test combinations. The purpose of this study was to accumulate a large single-institution cohort of revision total joint arthroplasty (rTJA) patients to determine the diagnostic utility of combination serum biomarkers to identify PJI. METHODS: A single institution longitudinal database was assessed to identify all patients who underwent rTJA from 2017 to 2020. There were 1,363 rTJA patients (715 rTKA patients and 648 rTHA patients) including 273 PJI cases (20%) analyzed. The PJI was diagnosed post-rTJA utilizing 2011 Musculoskeletal Infection Society (MSIS) criteria. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) were systematically collected for all patients. RESULTS: The rTKA combination markers of CRP + ESR (sensitivity: 78.3%, specificity: 88.8%, positive predictive value (PPV): 70.0%, negative predictive value (NPV): 92.5%), CRP + D-dimer (sensitivity: 60.5%, specificity: 92.6%, PPV: 63.4%, NPV: 91.7%), and CRP + IL-6 (sensitivity: 38.5%, specificity: 100.0%, PPV: 100.0%, NPV: 92.9%) all yielded higher specificity than CRP alone (sensitivity: 94.4%, specificity: 75.0%, PPV: 55.5%, NPV: 97.6%). Similarly, the rTHA combination markers of CRP + ESR (sensitivity: 70.1%, specificity: 88.8%, PPV: 58.1%, NPV: 93.1%), CRP + D-dimer (sensitivity: 57.1%, specificity: 90.1%, PPV: 43.2%, NPV: 94.1%), and CRP + IL-6 (sensitivity: 21.4%, specificity: 98.4%, PPV: 60.0%, NPV: 91.7%) all yielded higher specificity than CRP alone (sensitivity: 84.7%, specificity: 77.5%, PPV: 45.4%, NPV: 95.8%). CONCLUSION: Overall, in diagnosing PJI for both rTKA and rTHA, 2-marker combinations yielded higher specificity, while 3-marker combinations yielded higher sensitivity compared to CRP alone. However, compared to all 2-marker and 3-marker combinations, CRP demonstrated superior overall diagnostic utility. These findings suggest that routine combination testing of markers for PJI diagnosis may be excessive and an unnecessary use of resources, especially in resource-limited situations.

Pent-up demand for total shoulder arthroplasty prior to Medicare eligibility at age 65 years: evidence from a national patient database and national survey data.

BACKGROUND: Rising utilization rates of total shoulder arthroplasty (TSA) paired with an aging US population herald increased future economic burden. Previous research has demonstrated evidence of "pent-up demand" in health care (delaying medical care until financially able) accompanying insurance status changes. The purpose of this study was to determine pent-up demand for TSA in the years leading up to Medicare coverage at age 65 years while identifying key drivers underlying this trend, including socioeconomic status. METHODS: The incidence rates of TSA were evaluated using the 2019 National Inpatient Sample database. The observed increase in incidence between the ages of 64 years (pre-Medicare group) and 65 years (post-Medicare group) was compared with the expected increase. The expected frequency of TSA was subtracted from the observed frequency of TSA to calculate pent-up demand. Excess cost was calculated by multiplying pent-up demand by the median cost of TSA. The Medicare Expenditure Panel Survey-Household Component was used to compare health care cost and patient experience between pre-Medicare patients (aged 60-64 years) and post-Medicare patients (aged 66-70 years). RESULTS: The expected and observed increases in TSA procedures from age 64 years to age 65 years were 402, for an incidence rate increase of 0.13/1000 population (12.8% increase), and 820, for an incidence rate increase of 0.24/1000 population (27% increase), respectively. The 27% increase represented a sharp jump in comparison to the 7.8% annual growth rate between age 65 years and age 77 years. This resulted in pent-up demand between age 64 years and age 65 years of 418 TSA procedures and excess cost of $7.5 million. Mean total out-of-pocket expenses were significantly higher for the pre-Medicare group than for the post-Medicare group ($1700 vs. $1510, P < .001). Compared with the post-Medicare group, the pre-Medicare group exhibited a significantly higher proportion of patients who delayed Medicare care because of cost (P < .001), could not afford medical care (P < .001), had problems paying medical bills (P < .001), and were unable to pay medical bills (P < .001). Physician-patient relationship experience scores were significantly worse in the pre-Medicare group (P < .001). These trends were even stronger for low-income patients when data were broken down by income status. CONCLUSIONS: Patients likely delay elective TSA until reaching Medicare eligibility at age 65 years, resulting in substantial added financial burden to the health care system. As US health care costs continue to rise, it will be crucial for orthopedic providers and policy makers to be aware of pent-up demand for TSA and its possible associated drivers, especially socioeconomic status.

A Systematic Review of Lower-Body Kinematic and Strength Factors Associated With Pitch Velocity in Adult Baseball Pitchers.

CONTEXT: Ball velocity for baseball pitchers is influenced by a multitude of factors along the kinetic chain. While a vast amount of data currently exist exploring lower-extremity kinematic and strength factors in baseball pitchers, no previous study has systematically reviewed the available literature. OBJECTIVE: The aim of this systematic review was to perform a comprehensive assessment of the available literature investigating the association between lower-extremity kinematic and strength parameters and pitch velocity in adult pitchers. EVIDENCE ACQUISITION: Cross-sectional studies that investigated the association between lower-body kinematic and strength factors and ball velocity in adult pitchers were selected. A methodological index for nonrandomized studies checklist was used to evaluate the quality of all included studies. EVIDENCE SYNTHESIS: Seventeen studies met the inclusion criteria comprising a total of 909 pitchers (65%, professional, 33% college, and 3% recreational). The most studied elements were hip strength and stride length. The mean methodological index for nonrandomized studies score was 11.75 of 16 (range = 10-14). Pitch velocity was found to be influenced by several lower-body kinematic and strength factors including the following: (1) hip range of motion and strength of muscles around the hip and pelvis, (2) alterations in stride length, (3) alterations in lead knee flexion/extension, and (4) several pelvic and trunk spatial relationships throughout the throwing phase. CONCLUSIONS: Based on this review, we conclude that hip strength is a well-established predictor of increased pitch velocity in adult pitchers. Further studies in adult pitchers are needed to elucidate the effect of stride length on pitch velocity given mixed results across multiple studies. This study can provide a basis for trainers and coaches to consider the importance of lower-extremity muscle strengthening as a means by which adult pitchers can improve pitching performance.

Pharmacological Therapies for Connective Tissue Fibrosis in Orthopaedics.

Fibrosis is a common and debilitating pathological process that affects many organ systems and contributes to connective tissue disorders in orthopaedics. Tendons heal after acute and chronic injury through a process of fibrovascular scar tissue formation, and soft tissue joint capsules can be affected after traumatic joint injury, leading to arthrofibrosis. Although the precise underlying mechanisms are still being elucidated, fibrosis is thought to be a consequence of dysregulated immune and cytokine signaling that leads to myofibroblast activation and proliferation and subsequent excessive collagen deposition. Current treatments for connective tissue fibrosis include physical therapy and surgery, but there are no therapies that directly target the underlying cellular and molecular mechanisms of fibrosis. Many pharmacological agents have been used to successfully target fibrosis in other tissues and organ systems and thus are a promising treatment option to fill this gap. However, limited evidence is available to guide the use of these agents in musculoskeletal connective tissues. This article provides an overview of pharmacological therapies that have potential to treat connective tissue fibrosis in patients with musculoskeletal conditions, along with the current supporting evidence and future uses of each therapy.

Reasons and Risk Factors for Failed Same-Day Discharge After Primary Total Knee Arthroplasty.

BACKGROUND: As ambulatory total knee arthroplasty (TKA) becomes increasingly common, unplanned admission after surgery presents a challenge for the health care system. Studies evaluating the reasons and risk factors for this occurrence are limited. We sought to evaluate the reasons for unplanned admission after surgery and identify risk factors associated with this occurrence. METHODS: Patients registered in an institutional ambulatory joint arthroplasty program who underwent a TKA from 2017-2020 were retrospectively reviewed. The criteria for enrollment include candidates for unilateral TKA between the ages of 18 and 70 years, with a body mass index (BMI) of less than 35, and appropriate social and material support at home. Patients who had certain comorbidities including coronary artery disease, valvular heart disease, and opioid dependence were not eligible. A total of 274 patients who underwent TKA with planned same-day discharge (SDD) were identified in the medical record and reviewed. In this cohort, 140 patients (51.1%) were discharged on the day of surgery and 134 patients (48.9%) required a minimum 1-night admission. Demographics, comorbidities, and perioperative data were collected. Factors associated with failed SDD were identified using multivariate logistic regression. RESULTS: The most common reasons for failed SDD were failure to meet ambulation goals (25%) and logistical issues related to a late-day case (19%). Risk factors for failed SDD include general anesthesia (odds ratio (OR) 12.60, P = .047), procedure start time after 11:00 am (OR 5.16, P < .001), highest postoperative pain score >8 (visual analogue scale, OR 5.78, P = .001). Willingness to accept a higher pain threshold before discharge (visual analogue scale 4 to 10) was associated with successful SDD (OR 3.0, P < .001). Age and American Society of Anesthesiologists (ASA) classification were not associated with failed SDD. CONCLUSIONS: The most common reasons for failed SDD were related to logistical issues and postoperative mobilization. Risk factors for failed SDD involve case timing and pain control. Modifiable perioperative factors may play an important role in successful SDD after TKA.

Characterization and Potential Relevance of Randomized Controlled Trial Patient Populations in Total Joint Arthroplasty in the United States: A Systematic Review.

BACKGROUND: A substantial number of randomized controlled trial (RCT) studies in total joint arthroplasty (TJA) are published each year in the United States (US). However, it is unknown how closely the demographic and clinical characteristics of these cohorts resemble that of the US patient population undergoing TJA. Thus, the purpose of this systematic review was to evaluate the patient characteristics of published RCTs in TJA in the US and to compare these characteristics against patient cohorts from national patient databases. METHODS: RCT studies regarding primary TJA conducted in the US were selected. Key patient demographics were aggregated and compared against demographics characteristics of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality National Inpatient Sample (NIS) and American College of Surgeons National Surgical Quality Improvement Program patient cohorts. RESULTS: One hundred and fifty-three RCTs fulfilled the inclusion criteria and were included. The total number of patients in the 153 RCTs was 24,135 patients. The average age of patients in the TJA RCT cohort was 65 years (53-80) while the NIS cohort was 67 years (18-90) (d = 0.21, effect size = small). The average body mass index of the TJA RCT cohort was 30.8 (18.2-37.6) while the National Surgical Quality Improvement Program cohort was 31.9 (14.1-59.6) (d = 0.18, effect size = small). For TJA, effect sizes for age, body mass index BMI, sex, ethnicity, smoking, and diabetes were all small or very small. CONCLUSION: Overall, the US RCT patient cohort for TJA does not differ substantially from the general patient population undergoing TJA in the United States. Differences in demographic and clinical characteristics between the TJA RCT cohort and database cohorts ranged from minimal to small, suggesting that these differences are unlikely to impact clinical outcomes.

YouTube as a source of patient education information for elbow ulnar collateral ligament injuries: a quality control content analysis.

BACKGROUND: While online orthopedic resources are becoming an increasingly popular avenue for patient education, videos on YouTube are not subject to peer review. The purpose of this cross-sectional study was to evaluate the quality of YouTube videos for patient education in ulnar collateral ligament (UCL) injuries of the elbow. METHODS: A search of keywords for UCL injury was conducted through the YouTube search engine. Each video was categorized by source and content. Video quality, reliability, and accuracy were assessed by two independent raters using five metrics: (1) Journal of American Medical Association (JAMA) benchmark criteria (range 0-4) for video reliability; (2) modified DISCERN score (range 1-5) for video reliability; (3) Global Quality Score (GQS; range 1-5) for video quality; (4) ulnar collateral ligament-specific score (UCL-SS; range 0-16), a novel score for comprehensiveness of health information presented; and (5) accuracy score (AS; range 1-3) for accuracy. RESULTS: Video content was comprised predominantly of disease-specific information (52%) and surgical technique (33%). The most common video sources were physician (42%) and commercial (23%). The mean JAMA score, modified DISCERN score, GQS, UCL-SS, and AS were 1.8, 2.4, 1.9, 5.3, and 2.7 respectively. CONCLUSIONS: Overall, YouTube is not a reliable or high-quality source for patients seeking information regarding UCL injuries, especially with videos uploaded by non-physician sources. The multiplicity of low quality, low reliability, and irrelevant videos can create a cumbersome and even inaccurate learning experience for patients.

Patient Experience and Satisfaction with Telemedicine During Coronavirus Disease 2019: A Multi-Institution Experience.

Introduction: The coronavirus disease 2019 (COVID-19) heralded an unprecedented increase in telemedicine utilization. Our objective was to assess patient satisfaction with telemedicine during the COVID-19 era. Methods: Telemedicine visit data were gathered from Stanford Health Care (Stanford) and the Hospital for Special Surgery (HSS). Patient satisfaction data from HSS were captured from a Press-Ganey questionnaire between April 19, 2020, and December 12, 2020, whereas Stanford data were taken from a novel survey instrument that was distributed to all patients between June 22, 2020, and November 1, 2020. Participants: There were 60,550 telemedicine visits at Stanford, each linked with a postvisit survey. At HSS, there were 66,349 total telemedicine visits with 7,348 randomly linked with a postvisit survey. Main Outcomes and Measures: Two measures of patient satisfaction were used for this study: (1) a patient's "overall visit score" and (2) whether the patient indicated the highest possible "likelihood to recommend" (LTR) score (LTR top box score). Results: The LTR top box percentage at Stanford increased from 69.6% to 74.0% (p = 0.0002), and HSS showed no significant change (p = 0.7067). In the multivariable model, the use of a cell phone (adjusted odds ratio [aOR]: 1.18; 95% confidence interval [CI]: 1.12-1.23) and tablet (aOR: 1.15; 95% CI: 1.07-1.23) was associated with higher overall scores, whereas visits with interrupted connections (aOR: 0.49; 95% CI: 0.42-0.57) or help required to connect (aOR: 0.49; 95% CI: 0.42-0.56) predicted lower patient satisfaction. Conclusions: We present the largest published description of patient satisfaction with telemedicine, and we identify important telemedicine-specific factors that predict increased overall visit score. These include the use of cell phones or tablets, phone reminders, and connecting before the visit was scheduled to begin. Visits with poor connectivity, extended wait times, or difficulty being seen, examined, or understood by the provider were linked with reduced odds of high scores. Our results suggest that attention to connectivity and audio/visual definition will help optimize patient satisfaction with future telemedicine encounters.

Shoulder Lesions Do Not Increase Inflammatory Biomarkers in Patients Undergoing Surgery for Glenohumeral Instability: An Exploratory Study.

Circulating protein biomarkers have demonstrated utility as a diagnostic tool in predicting musculoskeletal disease severity, but their utility in the evaluation of shoulder lesions associated with shoulder instability is unknown. Thus, the purpose of this exploratory study was to determine whether preoperative biomarkers of cartilage turnover and inflammation are associated with specific shoulder lesions in shoulder instability. Thirty-three patients (29.9 ± 9.4 years of age, 4.5 ± 4.7 dislocations) undergoing surgical treatment for shoulder instability were assessed for the presence or absence of associated shoulder lesions. Biomarkers including cartilage oligomeric matrix protein (COMP), C-reactive protein (HS-CRP), interleukin-8 (IL-8), and macrophage inflammatory protein-1ß (MIP-1b) were collected at the time of surgery. Patients with Hill-Sachs lesions had a 31% increase in COMP plasma levels (p=0.046). No other significant differences were observed for COMP, HS-CRP, IL-8, and MIP-1b with any shoulder lesion including Hill-Sachs lesions, capsular injuries, bony Bankart lesions, and SLAP lesions. In conclusion, inflammatory biomarkers including HS-CRP, IL-8, and MIP-1b were not associated with specific shoulder lesions, while biomarkers of cartilage turnover (COMP) were only elevated in Hill-Sachs lesions. These findings suggest that these biomarkers may have limited utility as prognostic indicators in patients with shoulder instability, though large-scale and longitudinal studies are still necessary.

Changes in Orthopaedic diagnoses during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been accompanied by significant reductions in patient volumes for non-COVID-19-related conditions ranging from acute coronary syndrome to ischemic strokes to acute trauma. However, the impact of the COVID-19 pandemic on patient volumes for a broad range of orthopedic conditions remains unknown. The purpose of this study was to investigate the association of the COVID-19 pandemic with changes in patient volumes of 35 emergent (e.g. dislocations, open fractures), urgent (e.g. fractures), and nonurgent orthopedic conditions (e.g. osteoarthritis, sprains). METHODS: A retrospective interrupted time-series analysis of patient volumes was conducted for 35 orthopedic conditions based on ICD-10 diagnosis codes. Patient hospitalizations and new problem visits were aggregated across two institutions in New York state, including one urban tertiary care orthopedic hospital, one urban academic medical center, and all state outpatient facilities affiliated with the orthopedic institution. Patient volumes in the COVID-19 peak period (03/2020-05/2020) and COVID-19 recovery period (06/2020-10/2020) were compared against pre-COVID-19 vol (01/2018-02/2020). RESULTS: Overall, 169,047 cases were included in the analysis across 35 conditions with 3775 emergent cases, 6376 urgent cases, and 158,896 nonurgent cases. During the COVID-19 peak period, patient caseloads for 1 out of 7 emergent conditions (p = 0.02) and 26 out of 28 urgent and nonurgent conditions (p < 0.05) were significantly reduced compared to the pre-COVID-19 period. During the COVID-19 recovery period, patient volumes in 3 out of 13 emergent and urgent conditions (p < 0.03) and 11 out of 22 nonurgent conditions (p < 0.04) were decreased compared to pre-COVID-19 vol. CONCLUSIONS: This study found that the pandemic was associated with considerable changes in patient patterns for non-COVID-19 orthopedic conditions. The long-term effects of patient volume reductions on both patient outcomes and orthopedic health systems remain to be seen. LEVEL OF EVIDENCE: Cohort study; level of evidence IV.

Trends in Patient, Physician, and Public Perception of Ulnar Collateral Ligament Reconstruction Using Social Media Analytics.

BACKGROUND: Social media posts regarding ulnar collateral ligament (UCL) injuries and reconstruction surgeries have increased in recent years. PURPOSE: To analyze posts shared on Instagram and Twitter referencing UCL injuries and reconstruction surgeries to evaluate public perception and any trends in perception over the past 3 years. STUDY DESIGN: Cross-sectional study. METHODS: A search of a 3-year period (August 2016 and August 2019) of public Instagram and Twitter posts was performed. We searched for >22 hashtags and search terms, including #TommyJohn, #TommyJohnSurgery, and #tornUCL. A categorical classification system was used to assess the sentiment, media format, perspective, timing, accuracy, and general content of each post. Post popularity was measured by number of likes and comments. RESULTS: A total of 3119 Instagram posts and 267 Twitter posts were included in the analysis. Of the 3119 Instagram posts analyzed, 34% were from patients, and 28% were from providers. Of the 267 Twitter posts analyzed, 42% were from patients, and 16% were from providers. Although the majority of social media posts were of a positive sentiment, over the past 3 years, there was a major surge in negative sentiment posts (97% increase) versus positive sentiment posts (9% increase). Patients were more likely to focus their posts on rehabilitation, return to play, and activities of daily living. Providers tended to focus their posts on education, rehabilitation, and injury prevention. Patient posts declined over the past 3 years (-28%), whereas provider posts increased substantially (110%). Of posts shared by health care providers, 4% of posts contained inaccurate or misleading information. CONCLUSION: The majority of patients who post about their UCL injury and reconstruction on social media have a positive sentiment when discussing their procedure. However, negative sentiment posts have increased significantly over the past 3 years. Patient content revolves around rehabilitation and return to play. Although patient posts have declined over the past 3 years, provider posts have increased substantially with an emphasis on education.

Rates of self-directed perioperative cannabidiol use in patients undergoing total hip or knee arthroplasty.

Aim: To evaluate the prevalence of self-directed cannabidiol (CBD) use in patients with end-stage degenerative hip and knee arthritis who underwent total hip arthroplasty and total knee arthroplasty. Materials & methods: Anonymous surveys for 109 patients were completed at 6 weeks follow-up after either total hip arthroplasty or total knee arthroplasty at a single tertiary care US orthopedic hospital. Results: Within the perioperative window encompassing both preoperative and postoperative periods, 22% (95% CI: 14-30%) of patients used CBD. Conclusion: There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-directed perioperative CBD use and the mixed body of evidence, further research is needed to better understand whether CBD is safe and effective.

Lay abstract Aim: To evaluate the self-guided usage rate of cannabidiol (CBD) in patients with hip and knee arthritis who underwent hip and/or knee replacement surgery. Materials & methods: Anonymous surveys for 109 patients were completed 6 weeks after either hip or knee replacement surgery at a large US orthopedic hospital. Results: Among the 109 patients who underwent hip and/or knee replacement surgery, 22% (95% CI: 14­30%) of patients used CBD. Conclusion: There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-guided CBD use among patients undergoing hip or knee replacement surgery together with the mixed body of research, further research is needed to better understand whether CBD is safe and effective.

wtf genes are prolific dual poison-antidote meiotic drivers.

Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe. We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility.

Genome rearrangements and pervasive meiotic drive cause hybrid infertility in fission yeast.

Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Here we identify causes underlying hybrid infertility of two recently diverged fission yeast species Schizosaccharomyces pombe and S. kambucha, which mate to form viable hybrid diploids that efficiently complete meiosis, but generate few viable gametes. We find that chromosomal rearrangements and related recombination defects are major but not sole causes of hybrid infertility. At least three distinct meiotic drive alleles, one on each S. kambucha chromosome, independently contribute to hybrid infertility by causing nonrandom spore death. Two of these driving loci are linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. Our study reveals how quickly multiple barriers to fertility can arise. In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation.DOI: http://dx.doi.org/10.7554/eLife.02630.001.

Metabotropic glutamate receptors (mGluRs) regulate noxious stimulus-induced glutamate release in the spinal cord dorsal horn of rats with neuropathic and inflammatory pain.

In rats with persistent pain, spinal group I metabotropic glutamate receptor (mGluR) activity has been shown to be pronociceptive, whereas spinal group II/III activity is anti-nociceptive. In brain, group I mGluR activity produces positive feedback effects on glutamate release, whereas group II/III activity produces negative feedback effects. It is unknown whether the nociceptive versus anti-nociceptive effects of spinal group I versus group II/III mGluR activity depend on differential regulation of spinal glutamate release. Here, we used behavioral nociceptive testing and in vivo microdialysis to assess the effect of intrathecal treatment with group I mGluR antagonists [cyclopropan[b] chromen-1a-carboxylate, (CPCCOEt), 2-methyl-6-(phenylethynyl) pyridine (MPEP)] or groups II [aminopyrrolidine-2R,4R-dicarboxylate (APDC)] and III [l-2-amino-4-phosphonobutyrate (l-AP4)] mGluR agonists or vehicle, on nociception and noxious stimulus-induced increases in glutamate release in the spinal cord dorsal horn of rats with a chronic constriction injury (CCI) of the sciatic nerve or hind paw injection of complete Freund's adjuvant (CFA). None of the treatments significantly influenced basal spinal glutamate concentrations in either CCI or CFA rats. In CCI rats, formalin-induced nociception and increases in spinal glutamate concentrations were significantly attenuated by pre-treatment with CPCCOEt, MPEP, APDC, or l-AP4. In CFA rats, capsaicin-induced increases in nociception and spinal glutamate concentrations were significantly attenuated by pre-treatment with CPCCOEt, MPEP, or APDC, but not l-AP4. This study demonstrates that group I antagonists and group II/III mGluR agonists attenuated the enhanced nociception and noxious stimulus-induced glutamate release in spinal cord dorsal horn of CCI and/or CFA rats in vivo, and suggests a possible mechanism for their anti-hyperalgesic effects.

Evidence that pregabalin reduces neuropathic pain by inhibiting the spinal release of glutamate.

Pregabalin is an anti-convulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its anti-hyperalgesic action remains elusive. This study aims to help delineate pregabalin's anti-hyperalgesic mechanisms. We assessed the effectiveness of pregabalin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre- or post-treatment with systemic or intrathecal (i.t.) pregabalin at reducing the development and maintenance of the neuropathic pain symptoms. Pregabalin successfully decreased mechanical and cold hypersensitivity, as a pre-treatment, but was less effective at suppressing cold hypersensitivity when administered as a post-treatment. Furthermore, both i.t. and systemic administration of pregabalin were effective in reducing the behavioral hypersensitivity, with the exception of systemic post-treatment on cold hypersensitivity. We also examined pregabalin's effects at inhibiting hind paw formalin-induced nociception in naïve rats and formalin-induced release of excitatory amino acids in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. Pregabalin dose-dependently reduced nociceptive scores in the formalin test. We also present the first evidence that pregabalin reduces the formalin-induced release of glutamate in SCDH. Furthermore, i.t. pregabalin reduces the enhanced noxious stimulus-induced spinal release of glutamate seen in neuropathic rats. These data suggest that pregabalin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.

Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate.

Gabapentin is an anticonvulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its antihyperalgesic action remains elusive. This study aims to help delineate gabapentin's antihyperalgesic mechanisms. We assessed the effectiveness of gabapentin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre- or post-treatment with systemic or intrathecal (i.t.) gabapentin at reducing the development and maintenance of the neuropathic pain symptoms. Gabapentin successfully decreased mechanical and cold hypersensitivity, both as a pretreatment and post-treatment. Furthermore, both i.t. and systemic administration of gabapentin were effective in reducing the behavioral hypersensitivity; however, the i.t. administration was superior to the systemic. We also examined gabapentin's effects at inhibiting hindpaw formalin-induced release of excitatory amino acids (EAAs) in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. We present the first evidence that gabapentin reduces the formalin-induced release of both glutamate and aspartate in SCDH. Furthermore, i.t. gabapentin reduces the enhanced noxious stimulus-induced spinal release of glutamate seen in neuropathic rats. These data suggest that gabapentin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.

mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors, some of which are localized in the spinal cord dorsal horn, and are involved with pain perception. The anti-nociceptive effects of intrathecal (i.t.) pretreatment with various mGlu receptor agonists and antagonists were assessed in Long Evans rats with mechanical and thermal hypersensitivity after sub-dermal injection of capsaicin in the hindpaw. Selective group II (aminopyrrolidine-2R,4R-dicarboxylate, APDC) and group III (l-2-amino-4-phosphonobutyrate, L-AP4) agonists, as well as selective mGlu(1) (1-aminoindan-1,5(R,S)-dicarboxylic acid, AIDA) and mGlu(5) (2-methyl-6-(phenylethynyl)-pyridine, MPEP) receptor subtype antagonists were compared with that of an NMDA receptor antagonist (dizocilipine maleate, MK-801). The rats were observed for signs of capsaicin-induced mechanical and thermal hypersensitivity 15 min after capsaicin injection, and 20 min following i.t. drug administration. Results indicate there was a dose-dependent reduction in capsaicin-induced mechanical hypersensitivity for all mGlu receptor agents; with maximal increases in mechanical thresholds that were 7-fold for AIDA and APDC, 7.5-fold for L-AP4 and 5.6-fold for MPEP. However, only a weak reduction (often non-significant) in thermal hypersensitivity was observed with each of the mGlu receptor drugs; thermal latencies were maximally increased by 125% (AIDA), 0% (MPEP), 8% APDC and 205% (L-AP4). By contrast, the highest dose of MK-801 was able to significantly reduce both mechanical (maximal 6.67-fold increase in threshold) and thermal (maximal 3-fold increase in latencies) hyperalgesia. We conclude that mGlu receptors contribute to the development of mechanical allodynia, but not thermal hyperalgesia, following capsaicin injury; while iGluRs may contribute to both thermal and mechanical hypersensitivity.